Ramipril, (2S,3aS,6aS)-1[(S)—N—[(S)-1-carboxy-3-phenylpropyl]alanyl]octahydrocyclopenta[b]pyrrole-2-carboxylic acid, 1-ethyl ester is an angiotensin converting enzyme (ACE) inhibitor. Ramipril is used for the treatment of hypertension, heart failure, stroke, myocardial infarction, diabetes and cardiovascular disease.
Ramipril and the acid form, ramiprilat, is described in EP 0 097 022 B1.
The preparation of stable pharmaceutical formulations of ramipril is complicated since it is susceptible to certain types of degradation. Ramipril can undergo cyclization via internal nucleophilic attack to form substituted diketopiperazines and also degrade via hydrolysis and oxidation.
EP 1 501 546 A1 describes stable pharmaceutical formulation for combinations of a statin and an ACE inhibitor. The problem underlying the invention is that if an ACE inhibitor is in the presence of a stabilised statin, the ACE inhibitor decomposes to such extent that even after short storage period the content of decomposition products exceeds the permissible limit of degradation. EP 1 501 546 A1 provides a formulation wherein the statin and the ACE inhibitor are separated by physiologically acceptable inert material. Calcium sulfate is mentioned as a possible inorganic filler in the formulation but it is neither claimed nor mentioned in any example. In fact all the examples are concerned with three-layer tablet, wherein the statin layer and ACE inhibitor layer are separated by a layer of microcrystalline cellulose. The combination of the ACE inhibitor with a diuretic are not mentioned.
US 2003/0215526 claims formulations of ACE inhibitor a pharmaceutical composition comprising a therapeutically effective amount of an ACE inhibitor which is susceptible to degradation or its salt; a greater than stoichiometric amount of an alkali or alkaline earth metal carbonate, relative to the amount of ACE inhibitor or its salt, and a pharmaceutically acceptable carrier. The excipient calcium sulphate is not mentioned.
EP 0 280 999 B1 describes a composition comprising ACE inhibitor (i.e. ramipril), an alkali or alkaline earth metal carbonate and saccharide wherein the ACE inhibitor is stabilized against degradation (cyclization, discoloration and hydrolysis) by means of the other mentioned ingredients. In the specifications the relevant saccharides are lactose and mannitol. Modified starch is mentioned as disintegrant in the specification.
EP 0 317 878 B1 claims a stable, compressed pharmaceutical formulation containing a compound of a defined formula (i.e. ramipril) wherein, for stabilization before compression, a compound of the formula is a) coated with a polymeric, physiologically tolerated protective coating, or b) mixed with a physiologically tolerated buffer which ensures that a pH in the weakly acidic to weakly alkaline range is set up in a pharmaceutical formulation in the presence of moisture, where sodium bicarbonate is excepted as buffer, or c) mixed with a physiologically tolerated buffer which ensures that a pH in the weakly acid to weakly alkaline range is set up in a pharmaceutical formulation in the presence of moisture, and is coated with a polymeric, physiologically tolerated protective coating, where, in the case of stabilization according to b) with alkali metal or alkaline earth metal carbonate, the formulation is free of sugar.
WO 93/17685 claims combinations of ACE inhibitors and diuretics such as hydrochlorothiazide. Sodium hydrogen carbonate, pregelatinised starch and magnesium stearate are mentioned as excipients. Calcium sulphate is not mentioned.
Compositions of ramipril and piretamide is described in EP 215 357 B1. Calcium sulfate is not mentioned in this patent.
WO 03/028707 claims a formulation containing ramipril and lactose monohydrate. Calcium sulfate is mentioned in the specification as a possible diluent. Calcium sulfate is not included any example.